The goal of this SCOR is to take an interdisciplinary approach to studying an emerging and potentially important interaction between sex differences, hormonal status (e.g., progesterone - PRO), impulsivity, and drug-motivated behavior that could have important consequences for reducing two devastating forms of drug abuse, cigarette smoking and cocaine abuse. The central hypothesis is that reducing impulsivity will reduce drug-seeking behavior. Progesterone reduces impulsivity, and combined with drugs that have similar effects (e.g., atomoxetine - ATO), significant reductions in nicotine and cocaine abuse may be achieved. PRO will also be tested in combination with drugs that show some effect for nicotine dependence, varenicline (VAR) in the animal project. Based on a growing literature on sex differences in drug abuse, there may be sex differences in the effect of single and combined treatments. The following are the Specific Aims of the SCOR: 1. Investigate sex differences in the effect of exogenous PRO compared to placebo on impulsivity and smoking cessation in clinical Project 1. 2. To study sex differences in the effect of exogenous PRO vs. placebo in combination with ATO vs. placebo on impulsivity and relapse to cocaine abuse in clinical Project 2. 3. To examine sex differences in an animal model of nicotine and cocaine relapse and impulsivity for nicotine or cocaine in rats treated with PRO alone and in combination with ATO and VAR. Another goal is to study endogenous PRO effects on nicotine or cocaine self-administration in pregnant rats during gestation (high PRO) and lactation (low PRO) compared with males and no pregnant females. This SCOR allows for an interdisciplinary and translational approach to accomplishing these aims. It also offers economic efficiency, an opportunity to exchange ideas and approaches with others who are involved with the SCOR. PUBLIC HEALTH RELEVANCE: Despite much effort, there are not yet highly effective approved medications for the direct treatment of cocaine and nicotine dependence. This SCOR will carry out interdisciplinary and translational investigations to identify pharmacological interventions targeting behaviors impaired in nicotine and cocaine dependent subjects to enhance the effectiveness of existing behavioral treatments for addiction.